Submissions for variant NM_000038.6(APC):c.904C>T (p.Arg302Ter)

dbSNP: rs137854568

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164370	SCV000215005	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The p.R302* pathogenic mutation (also known as c.904C>T), located in coding exon 8 of the APC gene, results from a C to T substitution at nucleotide position 904. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has previously been reported in multiple individuals with attenuated or classic familial adenomatous polyposis (FAP) (Nishisho I et al. Science. 1991 Aug;253:665-9; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Kerr SE et al. J Mol Diagn. 2013 Jan;15(1):31-43; Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210154	SCV000266010	pathogenic	Colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV000000834	SCV000282851	pathogenic	Familial adenomatous polyposis 1	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg302*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis, Gardner syndrome, and colorectal cancer (PMID: 1651563, 11317365, 16317745, 20685668, 23159591, 23561487). ClinVar contains an entry for this variant (Variation ID: 798). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000077996	SCV000680600	pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 16317745, 25525159, 16134147, 20223039, 23757202, 1651563, 23561487, 8187091, 11317365, 23159591, 20685668, 12007223, 25801821, 15857185, 26917275, 20924072, 8162022, 26845104, 28127413, 26900293, 27623068, 28944238, 30897307, 32170310, 32603656, 31283021, 31942411, 31588418, 34600484, 30852976)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000499742	SCV000781068	pathogenic	Familial multiple polyposis syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000000834	SCV000838072	pathogenic	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077996	SCV000887556	pathogenic	not provided	2017-12-27	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of APC protein synthesis. In addition, it has been reported in individuals with familial adenomatous polyposis (FAP) and colorectal cancer in the published literature (PMIDs: 23561487 (2013), 23159591 (2013), and 1651563 (1991)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164370	SCV000905877	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000499742	SCV001361364	pathogenic	Familial multiple polyposis syndrome	2019-04-18	criteria provided, single submitter	clinical testing	Variant summary: APC c.904C>T (p.Arg302X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.1690C>T, p.Arg564X; c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; c.3340C>T, p.Arg1114X). The variant was absent in 251112 control chromosomes (gnomAD). The variant, c.904C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Friedl_2005, Rivera_2010, Lin_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000000834	SCV004044642	pathogenic	Familial adenomatous polyposis 1	2023-04-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000000834	SCV004207250	likely pathogenic	Familial adenomatous polyposis 1	2023-01-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996069	SCV004837341	pathogenic	Classic or attenuated familial adenomatous polyposis	2023-11-28	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with familial adenomatous polyposis (PMID: 8162022, 20924072, 15857185, 20223039, 23561487, 31942411, 30897307). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
OMIM	RCV000000834	SCV000020980	pathogenic	Familial adenomatous polyposis 1	1991-08-09	no assertion criteria provided	literature only
OMIM	RCV000000835	SCV000020985	pathogenic	Gardner syndrome	2006-11-30	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000077996	SCV000257037	pathogenic	not provided		no assertion criteria provided	research
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000000834	SCV000536922	pathogenic	Familial adenomatous polyposis 1	2016-06-11	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077996	SCV000591059	uncertain significance	not provided		no assertion criteria provided	clinical testing